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J. Biol. Chem., Vol. 280, Issue 16, 16278-16283, April 22, 2005

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Participation of Rip2 in Lipopolysaccharide Signaling Is Independent of Its Kinase Activity^*

Chafen Lu, Anlai Wang, Marion Dorsch, Jane Tian, Kumiko Nagashima, Anthony J. Coyle, Bruce Jaffee, Timothy D. Ocain, and Yajun Xu

From the Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139

Rip2 (Rick, Cardiak, CCK2, and CARD3) is a serine/threonine kinase containing a caspase recruitment domain (CARD) at the C terminus. Previous reports have shown that Rip2 is involved in multiple receptor signaling pathways that are important for innate and adaptive immune responses. However, it is not known whether Rip2 kinase activity is required for its function. Here we confirm that Rip2 participates in lipopolysaccharide (LPS)/Toll-like receptor (TLR4) signaling and demonstrate that its kinase activity is not required. Upon LPS stimulation, Rip2 was transiently recruited to the TLR4 receptor complex and associated with key TLR signaling mediators IRAK1 and TRAF6. Furthermore, Rip2 kinase activity was induced by LPS treatment. These data indicate that Rip2 is directly involved in the LPS/TLR4 signaling. Whereas macrophages from Rip2-deficient mice showed impaired NF-B and p38 mitogen-activated protein kinase activation and reduced cytokine production in response to LPS stimulation, LPS signaling was intact in macrophages from mice that express Rip2 kinase-dead mutant. These results demonstrate that Rip2-mediated LPS signaling is independent of its kinase activity. Our findings strongly suggest that Rip2 functions as an adaptor molecule in transducing signals from immune receptors.

Received for publication, September 2, 2004 , and in revised form, February 1, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: University of California, Berkeley, Molecular and Cell Biology, 16 Barker Hall MC 3202, Berkeley, CA 94720; Tel.: 617-212-3757; E-mail: chafenlu{at}berkeley.edu.

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